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VENOUS THROMBOEMBOLIC DISEASE. R. Duncan Hite, MD Section on Pulmonary and Critical Care Medicine. Venous Thromboembolic Disease. Venous thrombosis - ~ 5 million pts yearly Most caused by inadequate prophylaxis in hospitalized pts 10 % suffer pulmonary embolism ~ 500,000

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venous thromboembolic disease

VENOUS THROMBOEMBOLIC DISEASE

R. Duncan Hite, MD

Section on Pulmonary and Critical Care Medicine

venous thromboembolic disease1
Venous Thromboembolic Disease
  • Venous thrombosis - ~ 5 million pts yearly
      • Most caused by inadequate prophylaxis in hospitalized pts
  • 10 % suffer pulmonary embolism ~ 500,000
  • ~ 1% of all hospitalized pts have PE
  • Contributes to 6 % of all hospital deaths
  • ~ 125,000 deaths annually from PE
      • 3rd most common cardiovascular cause of death (MI, CVA)
      • Most deaths occur early – PREVENTION IS KEY!!
  • Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental
slide4

CASE 1

  • July 8 - 37 yo WM presents to the ED with right sided pleuritic chest pain x 24 hours. No fever or cough. Minimal SOB. Denies chest trauma.
    • PMH: bronchitis/sinusitis, Multiple Sclerosis x 5 years (uses cane, + muscle spasms - Rx’d Baclofen), Smoker
    • Exam: HR 107, BP 124/82, SaO2 93% (RA), Afeb, tenderness over R ribs, coarse breath sounds on R, normal LE’s.
    • Tests: Nml CBC, CXR w/ “vague” infiltrate in RUL
  • Dx: Costochondritis - Rx’d with NSAIDs
  • July 10 - F/U w/PCP - Dx’ed with pneumonia - Rx’d w/Biaxin
  • July 12 - returns to ED with presyncope, N/V - D/C’d home
    • - returns 2 hours later with PEA arrest and dies
    • - autopsy -- massive PE
slide5

CASE 2

  • Early June - 52 yo BM admitted for acute AMI requiring cardiac cath and PTCA of LAD. Requires mechanical ventilation x 5 days, ICU x 7 days and in hospital x 10 days. ECHO prior to d/c reveals EF of approx 25%.
  • Late June - pt readmitted for W/U of persistent leukocytosis noted on earlier admission. Undergoes BM Bx with findings consistent with CML. Discharged to home after 3 days.
  • Early July (5 days post d/c) - Seen in walk-in clinic for non-productive cough and SOB. CXR clear. Dx: bronchitis
  • Mid July - symptoms persist/worse. Repeat CXR reveals new LLL effusion. Dx’ed with CHF and given diuretics. + PPD.
  • Early August - referred to Pulmonary Clinic for persistent cough, SOB and effusion. ? CA v. TB.
slide6

CASE 3

- 43 yo AA male truck driver who has bilateral knee injuries while playing basketball. Requires bilateral knee repairs requiring fixation of both lower extremities for 6 - 8 weeks.

- Returns to the ED 4 weeks later with chest pain, SOB and hypoxemia. Has massive PE by CT angiogram and pulmonary hypertension/RV dilation by echocardiogram.

- Given TPA with good clinical response.

venous thromboembolic disease epidemiology
Venous Thromboembolic DiseaseEpidemiology
  • 85 - 90% of PE pts have DVT risk factors
  • 90-95% of PEs arise from lower ext. DVT
  • Defined DVT Risk Factors: (Virchow’s Triad)
    • Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos)
    • Venous Injury - Prior DVT/PE, LE Trauma/Surgery
        • LE trauma or surgery - Very high (50+%)
        • Major surgery - (5 - 8%)
    • Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking
slide8

 PAP

 PVR

 RV/RA

 CO

 RVEDV

 LVEDV

 CO

 HR

 BP

 SVR

Pulmonary Hypertension Hemodynamic Effects

deep venous thrombosis diagnosis
Deep Venous ThrombosisDiagnosis
  • Venography - remains the “gold standard”
      • Pitfalls: Difficult to perform, expensive, contrast load, DVT
  • Compression Ultrasound (Sonography, Duplex and Color Doppler)
      • Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image
      • Accuracy:
        • Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100%
        • High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100%
  • Impedance Plethysmography
  • Radionuclide Venography (Indium-111)
  • MRI - increasing popularity and utilization, includes deep pelvic veins
deep venous thrombosis prevention
Deep Venous ThrombosisPrevention
  • Orthopedic Surgery
    • LMWH or Coumadin (INR 2.0 - 3.0) beginning preoperatively or immediately postoperatively. Adjusted dose SQ Heparin is an acceptable alternative but more complex.
    • Adjuvant use of mechanical devices may add additional benefit. May be sufficient as primary prophylaxis for TKR if used optimally.
    • Low dose SQ Hep, Aspirin, IPC alone are not recommended (less effective).
    • Duration:
      • minimum of 7-10 days
      • Post Discharge Prophylaxis: 4-6 weeks for high risk patients

ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

deep venous thrombosis prevention1
Deep Venous ThrombosisPrevention
  • General Surgery (including Urologic)
    • Prophylaxis with SQHep, LMWH, ES or IPC
      • Moderate Risk - minor procedure with a risk factor or 40-60 yo, major procedures and <40
      • High Risk - minor procedure with risk factors or >60, major procedures with risk factors or age >40.
      • Increased Risk of Bleeding - use ES or IPC
    • Combination therapy: very high risk - multiple risk factors
    • Postdischarge Prophylaxis: selected very high risk pts

ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

deep venous thrombosis prevention2
Deep Venous ThrombosisPrevention
  • Gynecologic Surgery
    • Major surgery for benign disease
        • SQ Hep BID, LMWH, IPC, continue for several days post op
    • Major surgery for malignancy
        • SQ Hep TID, Combination AC/Mech, high dose LMWH
  • Neurosurgery
    • Intracranial Surgery
        • IPC or ES, Low dose SQHep or LMWH may be acceptable
        • Combination IPC or ES with SQHep or LMWH in high risk

ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

deep venous thrombosis prevention3
Deep Venous ThrombosisPrevention
  • Trauma
    • LMWH as soon as possible
    • IPC or ES until LMWH started
  • Acute Spinal Cord Injury
    • LMWH recommended
    • Low dose SQHep, ES or IPC are less effective
    • Combination Mechanical/anticoagulant may be acceptable
    • Continue throughout rehabilatation
  • Medical(Cancer, CHF, Bedrest, MI, CVA…)
    • Low dose SQ Hep or LMWH
    • IPC if anticoagulation contraindicated

ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

deep venous thrombosis prevention4
Deep Venous ThrombosisPrevention

Samama, etal NEJM, 1999, 341, 793.

deep venous thrombosis prevention5
Deep Venous ThrombosisPrevention

Samama, etal NEJM, 1999, 341, 793.

deep venous thrombosis prevention6
Deep Venous ThrombosisPrevention

Samama, etal NEJM, 1999, 341, 793.

deep venous thrombosis prevention7
Deep Venous ThrombosisPrevention

Samama, etal NEJM, 1999, 341, 793.

pe signs and symptoms
PE SIGNS AND SYMPTOMS

Symptoms

  • Dyspnea - 80%
  • Chest pain - 70%
  • Cough - 50%
  • Apprehension - 50%
  • Hemoptysis - 30%

Signs

  • Tachycardia - 60%
  • Tachypnea - 70%
  • Fever - 60%
  • Clinical DVT - 30%
pulmonary embolism diagnosis
Pulmonary EmbolismDiagnosis
  • Chest x-ray - nonspecific abnormalities in most; normal early
      • Westermark\'s sign and Hampton\'s hump uncommon
  • Arterial blood gas – hypoxemia is common
      • 15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient)
  • ECG – nonspecific changes typically
      • S1Q3T3 pattern in massive PE with RV strain
      • helpful in evaluating other causes of chest pain
pe v q lung scan
PE – V/Q LUNG SCAN
  • Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion
  • Safe
  • Not very specific
  • Not very useful if pre-existing lung disease
pulmonary embolism diagnosis v q scan
Pulmonary EmbolismDiagnosis - V/Q Scan

PIOPED. JAMA, 1990, 263, 2753.

pulmonary embolism clinical presentation d dimer
Pulmonary EmbolismClinical Presentation: D-dimer

Ginsberg, Ann Int Med, 1998, 129, 1006.

pulmonary embolism clinical presentation d dimer1
Pulmonary EmbolismClinical Presentation: D-dimer

Ginsberg, Ann Int Med, 1998, 129, 1006.

pulmonary embolism clinical presentation d dimer2
Pulmonary EmbolismClinical Presentation: D-dimer

Ginsberg, Ann Int Med, 1998, 129, 1006.

pulmonary embolism diagnosis pulmonary arteriogram
Pulmonary EmbolismDiagnosis - Pulmonary Arteriogram
  • Remains “gold standard” for Dx of PE
  • Expensive
  • Low morbidity and mortality
    • Mortality < 0.1%
    • Major morbidity < 0.5%
    • Pulmonary Hypertension not a contraindication
slide27

Pulmonary EmbolismDiagnosis - Pulmonary Arteriogram

Normal

Lobar Defect

Segmental Defect

slide29

Pulmonary EmbolismDiagnosis - Chest CT

  • Accurate for segmental or larger PE
      • Sensitivity 85 - 95% (Overall 50-60%)
      • Specificity 90 - 100%
  • Accuracy depends on interpreter
      • Large Inter-interpreter variability
      • Reduced accuracy with less experience
  • Significant contrast load ~ 65% of PA gram
  • Similar expense to Pulmonary Arteriogram
  • Can identify other pulmonary etiologies
slide30

Oudkerk, etal. Lancet, 2002, 359, 1643.

Pulmonary Emboli Diagnosis - MRA

venous thromboembolism treatment
Venous ThromboembolismTreatment

Continuous IV Heparin:

  • Begin when PE suspected - bolus dose
  • Continue for 7 - 10 days overlap with warfarin
  • Permits fibrinolytic system (plasmin) to lyse clot
  • Inhibits further clot formation / propagation
  • Give adequate dose!
    • Recurrence higher with lower doses
    • Weight based bolus with “protocol” for adjustments
  • Emphasis on PTT probably excessive
    • PTT not direct measure of antithrombotic effect
    • PTT does not correlate with bleeding complications
slide32

Heparin-Induced AntibodiesHITTS

  • Clinicopathologic Syndrome:
      • Unexplained  50% decrease in platelets (even if absolute total > 150)
      • Positive test for Heparin antibodies
          • Activation assay (more relevant but more difficult)
          • Antigen assay
  • Types:
    • Type I
      • begins early (few hours) after starting heparin
      • typically benign with plts usually staying > 100K. No Rx needed.
    • Type II
      • begins several days into treatment (unless previously sensitized)
      • High risk for thrombotic complications. Requires Rx.
venous thromboembolism treatment1

5,400

10,000

5,000

15,000

Molecular weight (daltons)

Venous ThromboembolismTreatment

Low Molecular Weight Heparins:

  • Dosing: (Lovenox)
    • Prophylaxis: 30 mg BID
    • Treatment: 1 mg/kg twice daily or 1.5 mg/kg qday (max 150 mg)
  • Less monitoring (Factor Xa assay)
    • Two Exceptions:
      • Obesity
      • Renal Failure
  • Cross Reactive with Heparin Antibodies
    • Possibly less immunogenic if used primarily
venous thromboembolism outpatient lmwh
Venous ThromboembolismOutpatient LMWH

$5,323

Total mean costs per patient (CAN)

P < 0.0001

95% CI $2,012 to $4,050

$2,278

Enoxaparin sodium

Unfractionated heparin

O’Brien et al. Arch Int Med. 1999;159:2298-2304.

venous thromboembolism treatment2
Venous ThromboembolismTreatment

Synthetic Heparins:

Fondaparinux (Arixtra)

  • Trials:
    • DVT Prevention in Orthopedic Surgery

Lancet, 2002, 359, 1715-26

  • Dosing:
    • Prophylaxis: 2.5 mg qday
  • Less monitoring (Factor Xa assay)
    • Not recommended in renal failure
  • Does not cause Heparin Antibodies (??)
venous thromboembolism treatment3
Venous ThromboembolismTreatment

Oral anticoagulation (Coumadin):

  • Inhibits synthesis of Vitamin K dependent factors
    • PT sensitive to Factor VII - short half-life -correlates with bleeding risk
    • Thrombosis related to Factors II and X - longer half-life
  • Overlap with heparin or LMWH until PT therapeutic for 3 - 5 days
    • Coumadin decreases Protein C and S levels more quickly
  • Warfarin load (high dose) not useful
  • Target INR range = 2.0 - 3.0
  • Continue anticoagulation for 4 - 6 months
venous thromboembolism treatment4
Venous ThromboembolismTreatment

Oral anticoagulation (Ximelagatran):

  • Direct Thrombin inhibitor
  • BID oral therapy
  • Does not require dose monitoring

Francis, etal. Ann Int Med,, 2002, 137, 648.

slide38

Venous ThromboembolismTreatment - Thrombolytics

  • Massive Pulmonary Embolism
    • Significant hemodynamic compromise present
    • Evidence of RV failure on Echocardiogram
      • Controversial
  • Phlegmasia Cerulea Dolens
  • Agents studied
    • Streptokinase - 250,000 U load; 100,000 U/hr x 24hrs
    • Urokinase - 4,400 U load; 2,200 U/hr x 12 hrs
    • tPA - 100mg over 2 hrs
slide39

Pulmonary EmbolismTreatment - Thrombolytics

Konstantinides, etal. N Engl J Med, 2002, 347, 1143.

slide40

Inferior Vena Cava Filter

  • Indications:
    • Intolerance to anticoagulation**
    • Recurrent PE despite adequate anticoagulation
    • Chronic PE with Pulm HTN
    • Surgical removal of acute or chronic PE
    • Massive PE (?)
  • Outcomes:
    •  PE rate,  DVT rate, Mortality unchanged
    • Decousos, etal. (NEJM, 1998, 338, 409) - no benefit
      • Pts with contraindication/failure of anticoagualtion excluded
  • CONTINUE ANTICOAGULATION! - if possible

Ballew etal. Clin Chest Med, 1995, 16, 295.

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